ITMI20130392A1 - SYNTHESIS OF A SEROTONIN REPLACEMENT INHIBITOR - Google Patents
SYNTHESIS OF A SEROTONIN REPLACEMENT INHIBITORInfo
- Publication number
- ITMI20130392A1 ITMI20130392A1 IT000392A ITMI20130392A ITMI20130392A1 IT MI20130392 A1 ITMI20130392 A1 IT MI20130392A1 IT 000392 A IT000392 A IT 000392A IT MI20130392 A ITMI20130392 A IT MI20130392A IT MI20130392 A1 ITMI20130392 A1 IT MI20130392A1
- Authority
- IT
- Italy
- Prior art keywords
- formula
- compound
- group
- iii
- salt
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 238000003786 synthesis reaction Methods 0.000 title description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 6
- 229940076279 serotonin Drugs 0.000 title description 3
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000006722 reduction reaction Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 238000006276 transfer reaction Methods 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- GJXZGYIBRJJFHN-UHFFFAOYSA-N 3-(4-hydroxybutyl)-1-(4-methylphenyl)sulfonylindole-5-carbonitrile Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC=C(C#N)C=C2C(CCCCO)=C1 GJXZGYIBRJJFHN-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- -1 piperazine compound Chemical class 0.000 description 10
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 description 10
- 229960003740 vilazodone Drugs 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 229910002666 PdCl2 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 description 2
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 2
- IUOBIBLYALVHRN-UHFFFAOYSA-N 3-iodo-1-(4-methylphenyl)sulfonylindole-5-carbonitrile Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC=C(C#N)C=C2C(I)=C1 IUOBIBLYALVHRN-UHFFFAOYSA-N 0.000 description 2
- LCQFJLARYCQCQR-UHFFFAOYSA-N 3-iodo-1h-indole-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(I)=CNC2=C1 LCQFJLARYCQCQR-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010054089 Depressive symptom Diseases 0.000 description 2
- 238000007341 Heck reaction Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- LRMLRDZWDVUKTE-UHFFFAOYSA-N ethyl 5-[4-[4-[5-cyano-1-(4-methylphenyl)sulfonylindol-3-yl]butyl]piperazin-1-yl]-1-benzofuran-2-carboxylate Chemical compound C=1C=C2OC(C(=O)OCC)=CC2=CC=1N(CC1)CCN1CCCCC(C1=CC(=CC=C11)C#N)=CN1S(=O)(=O)C1=CC=C(C)C=C1 LRMLRDZWDVUKTE-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000000852 hydrogen donor Substances 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 102000017911 HTR1A Human genes 0.000 description 1
- 101150015707 HTR1A gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- QLFNUXTWJGXNLH-UHFFFAOYSA-N bis(2-methoxyethoxy)alumane Chemical compound COCCO[AlH]OCCOC QLFNUXTWJGXNLH-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZKLDXJIVWKPASZ-UHFFFAOYSA-N ethyl 5-piperazin-1-yl-1-benzofuran-2-carboxylate Chemical compound C=1C=C2OC(C(=O)OCC)=CC2=CC=1N1CCNCC1 ZKLDXJIVWKPASZ-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Cosmetics (AREA)
Description
“SINTESI DI UN INIBITORE DELLA RICAPTAZIONE DELLA SEROTONINA†⠀ œSUMMARY OF A SEROTONIN RECAPTABLE INHIBITORâ €
CAMPO TECNICO DELL’INVENZIONE TECHNICAL FIELD OF INVENTION
La presente invenzione riguarda un nuovo procedimento per la preparazione di Vilazodone, e dei suoi intermedi, avente nota attività come inibitore della ricaptazione della serotonina ed impiegato nel trattamento di gravi sintomi depressivi. The present invention relates to a new process for the preparation of Vilazodone, and its intermediates, having known activity as a serotonin reuptake inhibitor and used in the treatment of severe depressive symptoms.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
Il 5-(4-[4-(5-ciano-1H-indol-3-il)butil]piperazin-1-il)benzofuran-2-carbossammide di formula (I), noto anche come Vilazodone, à ̈ un inibitore della ricaptazione della serotonina e agisce come agonista parziale dei recettori 5-HT1A. Detto composto à ̈ commercializzato come sale cloridrato ed utilizzato per il trattamento di gravi sintomi depressivi negli adulti, in dosi di 10, 20 e 40 mg. 5- (4- [4- (5-cyano-1H-indole-3-yl) butyl] piperazin-1-yl) benzofuran-2-carboxamide of formula (I), also known as Vilazodone, is an inhibitor reuptake of serotonin and acts as a partial agonist of 5-HT1A receptors. Said compound is marketed as a hydrochloride salt and used for the treatment of severe depressive symptoms in adults, in doses of 10, 20 and 40 mg.
NONO
CONH2CONH2
N No.
N No.
N No.
H H.
(I) (THE)
Vilazodone à ̈ noto da US 5,532,241, che ne descrive anche la sintesi (Schema 1) mediante un procedimento che prevede l’alchilazione del derivato piperazinico di formula A con un agente alchilante di formula B ad ottenere il composto piperazinico di formula C, che dopo conversione del gruppo funzionale carbossilico in ammidico primario porta al Vilazodone. Vilazodone is known from US 5,532,241, which also describes its synthesis (Scheme 1) by means of a process which provides for the alkylation of the piperazine derivative of formula A with an alkylating agent of formula B to obtain the piperazine compound of formula C, which after conversion of the carboxylic functional group into primary amide leads to Vilazodone.
N O COZ N N O COZ N
Cl H N Cl H N
N No.
H B A, Z = OH H B A, Z = OH
A', Z = OEt A ', Z = OEt
NONO
COZ COZ
N No.
N No.
C, Z = OH C, Z = OH
N C', Z = OEt N C ', Z = OEt
H (I), Z= NH2H (I), Z = NH2
Schema 1 Scheme 1
Nel J. Med. Chem. 2004, 47, 4684-4692 gli stessi ricercatori di US 5,532,241 propongono invece l’alchilazione della piperazina di formula A’ che fornisce il derivato estereo C’, il quale porta a Vilazodone dopo conversione del gruppo funzionale estereo in ammidico. Per quanto riguarda la sintesi delle piperazine di formula A ed A’, in letteratura sono stati descritti numerosi esempi di preparazione abbastanza efficienti, oltre a quello riportato in J. Med. Chem. 2004, 47, 4684-4692, sopra citato. In J. Med. Chem. 2004, 47, 4684-4692 the same researchers of US 5,532,241 propose instead the alkylation of piperazine of formula Aâ € ™ which provides the ester derivative Câ € ™, which leads to Vilazodone after conversion of the ester functional group into amide. As regards the synthesis of piperazines of formula A and Aâ € ™, numerous examples of quite efficient preparation have been described in the literature, in addition to the one reported in J. Med. Chem. 2004, 47, 4684-4692, cited above.
La preparazione di un agente alchilante come quello di formula B Ã ̈ invece piuttosto complessa e dispendiosa a livello industriale. On the other hand, the preparation of an alkylating agent such as that of formula B is rather complex and expensive on an industrial level.
In J. Med. Chem. 2004, 47, 4684-4692, infatti, B viene ottenuto per riduzione del derivato carbonilico D in accordo allo schema sintetico sotto riportato (Schema 2): In J. Med. Chem. 2004, 47, 4684-4692, in fact, B is obtained by reducing the carbonyl derivative D according to the synthetic scheme below (Scheme 2):
N No.
N N N N
ENO H ENO H
Cl Cl O Cl Cl O
N No.
Cl N Cl H D HBCl N Cl H D HB
F F.
Schema 2 Scheme 2
Detto composto di formula D Ã ̈ a sua volta preparato mediante reazione di Friedel Crafts del 5-cianoindolo di formula E con il clorobutirroil cloruro di formula F, entrambi commercialmente disponibili. Said compound of formula D is in turn prepared by Friedel Crafts reaction of 5-cyanoindole of formula E with chlorobutyroyl chloride of formula F, both commercially available.
La riduzione del derivato carbonilico D viene effettuata col costoso bis-(2-metossietossi)alluminio idruro, pure noto come Vitride/Red Al, con una resa del 26% dopo purificazione cromatografica. The reduction of the carbonyl derivative D is carried out with the expensive bis- (2-methoxyethoxy) aluminum hydride, also known as Vitride / Red Al, with a yield of 26% after chromatographic purification.
Molto recentemente à ̈ stato invece pubblicato un articolo su Org. Process. Res. Dev. 2012, 16, 1552-1557 in cui per ovviare a questo problema, gli autori hanno provato una serie di sistemi riducenti ed identificano nel sistema NaBH4/acido trifluoroacetico (TFA) in diclorometano quello migliore a fornire il prodotto B con una resa del 95%. Very recently an article was published on Org. Process. Res. Dev. 2012, 16, 1552-1557 in which to overcome this problem, the authors have tried a series of reducing systems and identify in the NaBH4 / trifluoroacetic acid (TFA) system in dichloromethane the best one to provide product B with a yield of 95% .
A ben analizzare il procedimento di riduzione sopra riportato, à ̈ però da mettere in rilievo che lo stesso à ̈ molto costoso, proprio per l’uso del TFA come cosolvente e di un solvente clorurato come solvente di reazione. In aggiunta e non meno importante, gli inventori della presente invenzione hanno verificato che, dal punto di vista della sicurezza, detta reazione nelle condizioni sopra riportate à ̈ altamente energetica. Pertanto, quando in laboratorio à ̈ stata provata l’aggiunta di NaBH4alla miscela di reazione, la reazione à ̈ risultata altamente esotermica e violenta e quindi molto pericolosa per gli operatori. Tale metodo non à ̈ quindi idoneo alla preparazione su scala industriale. A careful analysis of the reduction procedure reported above, however, should be pointed out that it is very expensive, precisely due to the use of TFA as a cosolvent and a chlorinated solvent as a reaction solvent. In addition and not least, the inventors of the present invention have verified that, from the point of view of safety, said reaction in the above conditions is highly energetic. Therefore, when the addition of NaBH4 to the reaction mixture was tested in the laboratory, the reaction was highly exothermic and violent and therefore very dangerous for the operators. This method is therefore not suitable for preparation on an industrial scale.
Esiste quindi la necessità di un metodo di preparazione alternativo più semplice e vantaggioso per preparare Vilazodone di formula (I). Tale nuovo metodo dovrebbe in particolare prevedere l’impiego di intermedi più facilmente sintetizzabili e purificabili su scala industriale, ottenibili con processi economici e sicuri per l’uomo e l’ambiente, preferibilmente catalitici, in maniera da ottenere il Vilazodone di formula (I) con alta resa ed efficienza. There is therefore a need for a simpler and more advantageous alternative preparation method to prepare Vilazodone of formula (I). This new method should in particular provide for the use of intermediates more easily synthesized and purifiable on an industrial scale, obtainable with economical and safe processes for man and the environment, preferably catalytic, in order to obtain the Vilazodone of formula (I) with high yield and efficiency.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
E’ stato qui sorprendentemente trovato che un composto di formula (II) It has been surprisingly found here that a compound of formula (II)
N No.
X X
N No.
P (II) P (II)
dove X à ̈ un gruppo –OH oppure un gruppo uscente e P à ̈ H oppure un gruppo protettivo dell’azoto indolico, può essere vantaggiosamente preparato mediante un procedimento comprendente la riduzione di un composto di formula (III) o (IV) where X is a group â € “OH or a leaving group and P à ̈ H or a protective group of indole nitrogen, can be advantageously prepared by a process comprising the reduction of a compound of formula (III) or (IV )
N N X N N X
X X
N No.
N (III) P N (III) P
P (IV) P (IV)
dove X e P sono come sopra definiti e dove il doppio legame -C=C-sulla catena alifatica può essere a stereochimica (E) o (Z) o una loro miscela, e, se desiderato, la conversione di un composto di formula (II) così ottenuto in un altro composto di formula (II). where X and P are as defined above and where the double bond -C = C-on the aliphatic chain can be a stereochemistry (E) or (Z) or a mixture thereof, and, if desired, the conversion of a compound of formula ( II) thus obtained in another compound of formula (II).
Detti composti di formula (III) e (IV) sono nuovi e sono pure oggetto dell’invenzione. Said compounds of formula (III) and (IV) are new and are also the subject of the invention.
Tale reazione di riduzione in accordo al procedimento dell’invenzione à ̈ particolarmente vantaggiosa in quanto à ̈ controllabile, sicura ed economica, le condizioni di reazione sono particolarmente blande e il composto desiderato di formula (II) à ̈ ottenuto in alta resa e purezza chimica. Per tale motivo, Vilazodone di formula (I), o un suo sale, ottenuto facendo uso degli intermedi e del procedimento di cui alla presente invenzione à ̈ prodotto in elevata resa e purezza chimica. This reduction reaction according to the process of the invention is particularly advantageous as it is controllable, safe and economical, the reaction conditions are particularly mild and the desired compound of formula (II) is obtained in high yield and purity. chemistry. For this reason, Vilazodone of formula (I), or a salt thereof, obtained by making use of the intermediates and the process of the present invention is produced in high yield and chemical purity.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Oggetto della presente invenzione à ̈ un procedimento per la preparazione di un composto di formula (II) The object of the present invention is a process for the preparation of a compound of formula (II)
N No.
X X
N No.
P (II) P (II)
X à ̈ un gruppo -OH oppure un gruppo uscente e P à ̈ H oppure un gruppo protettivo dell’azoto indolico, comprendente la riduzione di un composto di formula (III) o di un composto di formula (IV) X is a -OH group or a leaving group and P is H or a protective group of indole nitrogen, comprising the reduction of a compound of formula (III) or of a compound of formula (IV)
X X
X X
N N N N
P P P P
(III) (IV) (III) (IV)
dove X e P sono come sopra definiti, e, se desiderato, la conversione di un composto di formula (II) in un altro composto di formula (II). where X and P are as defined above, and, if desired, the conversion of a compound of formula (II) into another compound of formula (II).
In un composto di formula (III) il doppio legame -C=C- sulla catena alifatica può essere a stereochimica (E) o (Z), o una loro miscela. In a compound of formula (III) the double bond -C = C- on the aliphatic chain can be a stereochemistry (E) or (Z), or a mixture of them.
Un gruppo uscente à ̈ ad esempio un atomo di alogeno, preferibilmente cloro o iodio, oppure un gruppo OSO2R, dove R à ̈ un gruppo C1-C6alchile lineare o ramificato opzionalmente sostituito, un gruppo arile opzionalmente sostituito oppure eteroarile opzionalmente sostituito. Un gruppo C1-C6alchile à ̈ preferibilmente un gruppo C1-C4alchile, quale metile, etile o butile, che può essere sostituito da uno o più sostituenti scelti indipendentemente tra alogeno e fenile a sua volta opzionalmente sostituito da alogeno o nitro, tipicamente trifluorometile, nonafluorobutile, benzile, p-bromobenzile e p-nitrobenzile. Un gruppo arile può essere ad esempio fenile opzionalmente sostituito da un gruppo C1-C4alchile, ed à ̈ preferibilmente p-tolile. Un gruppo eteroarile può essere ad esempio N-imidazolo. Detto gruppo uscente à ̈ preferibilmente metansolfonile. A leaving group is for example a halogen atom, preferably chlorine or iodine, or an OSO2R group, where R is an optionally substituted linear or branched C1-C6alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group. A C1-C6alkyl group is preferably a C1-C4alkyl group, such as methyl, ethyl or butyl, which can be replaced by one or more substituents independently selected from halogen and phenyl in turn optionally replaced by halogen or nitro, typically trifluoromethyl, nonafluorobutyl , benzyl, p-bromobenzyl and p-nitrobenzyl. An aryl group can be for example phenyl optionally substituted by a C1-C4alkyl group, and is preferably p-tolyl. A heteroaryl group can be for example N-imidazole. Said leaving group is preferably methanesulfonyl.
Più preferibilmente X à ̈ un gruppo -OH oppure metansolfonile. More preferably X is a -OH or methanesulfonyl group.
Un gruppo protettivo dell’azoto indolico à ̈ un gruppo protettivo della funzionalità amminica ben noto alla persona esperta del ramo. L’azoto indolico può essere ad esempio protetto come gruppo funzionale carbammato, ammide o solfonammide. Un gruppo protettivo P à ̈ ad esempio tertbutilossicarbonile (Boc) o benzilossicarbonile (Cbz) o un gruppo OSO2P’, dove P’ à ̈ ad esempio, metile, etile, fenile, benzile, p-tolile, trifluorometile, preferibilmente P à ̈ un gruppo p-toluensolfonile. An indole nitrogen protective group is a protective group of amino functionality well known to the person skilled in the art. Indole nitrogen can, for example, be protected as a carbamate, amide or sulfonamide functional group. A protective group P is for example tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz) or an OSO2Pâ € ™ group, where Pâ € ™ is for example, methyl, ethyl, phenyl, benzyl, p-tolyl, trifluoromethyl, preferably P à ̈ a p-toluenesulfonyl group.
La riduzione di un composto di formula (III) oppure di formula (IV) può essere effettuata ad esempio per idrogenazione catalitica in presenza di un catalizzatore metallico omogeneo o eterogeneo, ad esempio a base di Pd, Pt, Ni, Rh o Ru, preferibilmente a base di Pd. Quando il catalizzatore metallico à ̈ eterogeneo, esso à ̈ preferibilmente depositato su un supporto inerte quale, ad esempio, carbone, bario idrossido, allumina, calcio carbonato; preferibilmente carbone. Preferibilmente il catalizzatore metallico à ̈ Pd(OH)2/C. The reduction of a compound of formula (III) or of formula (IV) can be carried out for example by catalytic hydrogenation in the presence of a homogeneous or heterogeneous metal catalyst, for example based on Pd, Pt, Ni, Rh or Ru, preferably based on Pd. When the metal catalyst is heterogeneous, it is preferably deposited on an inert support such as, for example, coal, barium hydroxide, alumina, calcium carbonate; preferably coal. Preferably the metal catalyst is Pd (OH) 2 / C.
La concentrazione del metallo sul supporto può variare tra circa l’1 ed il 30%, preferibilmente tra circa il 5 ed il 20%. The metal concentration on the support can vary between about 1 and 30%, preferably between about 5 and 20%.
La pressione di idrogeno impiegata può variare tra circa 1 atm e 10 atm, preferibilmente la reazione à ̈ condotta a pressione atmosferica. The hydrogen pressure used can vary between about 1 atm and 10 atm, preferably the reaction is carried out at atmospheric pressure.
La quantità molare di catalizzatore impiegata, riferita al composto di formula (II), à ̈ compresa tra circa lo 0,1 ed il 10%, preferibilmente tra circa lo 0,5 ed il 5%. The molar quantity of catalyst used, referred to the compound of formula (II), is comprised between about 0.1 and 10%, preferably between about 0.5 and 5%.
La reazione può essere condotta in presenza di un solvente organico, scelto, ad esempio, tra un solvente polare aprotico, tipicamente dimetilformammide, dimetilacetammide, acetonitrile, dimetilsolfossido; un etere ciclico o aciclico, tipicamente tetraidrofurano o diossano o metiltertbutil etere; un solvente clorurato, tipicamente diclorometano; un solvente apolare aprotico, tipicamente toluene o esano; un solvente polare protico, quale un C1-C6alcanolo lineare o ramificato, in particolare metanolo, etanolo, isopropanolo o butanolo, oppure acqua; un estere, ad esempio acetato di etile, acetato di isopropile, acetato di butile; un C3-C7chetone lineare o ramificato, ad esempio acetone, metil-etil chetone, metil isobutil chetone; un acido carbossilico, ad esempio acido acetico o acido propionico; o miscele di due o più di detti solventi, preferibilmente 2 o 3. In alternativa, la reazione può essere condotta in una soluzione di un acido minerale, ad esempio acido cloridrico o acido solforico, o una sua miscela con uno, due o tre dei solventi organici sopra elencati. Preferibilmente la reazione può essere condotta in un alcanolo, come sopra definito, o miscele di più alcanoli, o loro miscele con acqua, oppure in una miscela acetonitrile/acqua; più preferibilmente la riduzione à ̈ condotta in metanolo. The reaction can be carried out in the presence of an organic solvent, chosen, for example, from an aprotic polar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide; a cyclic or acyclic ether, typically tetrahydrofuran or dioxane or methyltertbutyl ether; a chlorinated solvent, typically dichloromethane; an aprotic apolar solvent, typically toluene or hexane; a polar protic solvent, such as a linear or branched C1-C6 alkanol, in particular methanol, ethanol, isopropanol or butanol, or water; an ester, for example ethyl acetate, isopropyl acetate, butyl acetate; a linear or branched C3-C7 ketone, for example acetone, methyl-ethyl ketone, methyl isobutyl ketone; a carboxylic acid, for example acetic acid or propionic acid; or mixtures of two or more of said solvents, preferably 2 or 3. Alternatively, the reaction can be carried out in a solution of a mineral acid, for example hydrochloric acid or sulfuric acid, or a mixture thereof with one, two or three of the organic solvents listed above. Preferably the reaction can be carried out in an alkanol, as defined above, or mixtures of several alkanols, or their mixtures with water, or in an acetonitrile / water mixture; more preferably the reduction is carried out in methanol.
Detta reazione di riduzione di un composto di formula (III) o (IV), come sopra definiti, può essere condotta ad una temperatura compresa tra circa 0°C e la temperatura di riflusso del solvente à ̈ preferibilmente tra circa 0°C e temperatura ambiente. Said reduction reaction of a compound of formula (III) or (IV), as defined above, can be carried out at a temperature between about 0 ° C and the reflux temperature of the solvent is preferably between about 0 ° C and temperature environment.
La reazione di riduzione di un composto di formula (III) oppure di formula (IV) può anche essere condotta mediante reazione di transfer di idrogeno, impiegando un catalizzatore metallico omogeneo o eterogeneo, ad esempio come sopra definito e nella stessa quantità molare, ed un donatore di idrogeno. Questo ultimo scelto ad esempio nel gruppo comprendente cicloesene, cicloesadiene, metilcicloesene, limonene, dipentene, mentene, idrazina, acido fosfinico o suoi derivati, ad esempio sodio ipofosfito, indolina, acido ascorbico, acido formico o suoi sali di sodio o ammonio, ed alcoli secondari, ad esempio l’isopropanolo. Preferibilmente ammonio formiato. The reduction reaction of a compound of formula (III) or of formula (IV) can also be carried out by means of a hydrogen transfer reaction, using a homogeneous or heterogeneous metal catalyst, for example as defined above and in the same molar quantity, and a hydrogen donor. The latter selected for example from the group comprising cyclohexene, cyclohexadiene, methylcyclohexene, limonene, dipentene, mentene, hydrazine, phosphinic acid or its derivatives, for example sodium hypophosphite, indoline, ascorbic acid, formic acid or its sodium or ammonium salts, and alcohols secondary, for example isopropanol. Preferably ammonium formate.
Il rapporto molare tra il donatore di idrogeno ed il composto di formula (III), oppure di formula (IV), può essere compreso tra circa 1,5 e 50, preferibilmente tra circa 1,5 e 10. The molar ratio between the hydrogen donor and the compound of formula (III), or of formula (IV), can be comprised between about 1.5 and 50, preferably between about 1.5 and 10.
La reazione di riduzione in transfer di idrogeno può essere condotta in presenza di un solvente organico, scelto ad esempio tra uno dei solventi sopra menzionati. The hydrogen transfer reduction reaction can be carried out in the presence of an organic solvent, chosen for example from one of the solvents mentioned above.
La conversione di un composto di formula (II) in un altro composto di formula (II) può essere effettuata in accordo a metodi noti, ad esempio un composto di formula (II) dove X à ̈ -OH può essere convertito in un composto di formula (II) dove X à ̈ -OSO2CH3, per reazione con metansolfonil cloruro in presenza di una base organica, quale ad esempio un’ammina terziaria, in particolare trietilammina, diisopropiletilammina, o di una base inorganica, quale, ad esempio, potassio carbonato. The conversion of a compound of formula (II) into another compound of formula (II) can be carried out according to known methods, for example a compound of formula (II) where X is -OH can be converted into a compound of formula (II) where X is -OSO2CH3, by reaction with methanesulfonyl chloride in the presence of an organic base, such as for example a tertiary amine, in particular triethylamine, diisopropylethylamine, or of an inorganic base, such as, for example, potassium carbonate.
Un ulteriore oggetto della presente invenzione à ̈ l’uso come intermedio di un composto di formula (II), dove X à ̈ un gruppo uscente come sopra definito e P à ̈ H oppure un gruppo protettivo come sopra definito, preparato in accordo all’invenzione, nella preparazione di un composto di formula (I), cioà ̈ Vilazodone. A further object of the present invention is the use as an intermediate of a compound of formula (II), where X is a leaving group as defined above and P is H or a protective group as defined above, prepared in accordance with € ™ invention, in the preparation of a compound of formula (I), namely Vilazodone.
In particolare, un composto di formula (I), o un suo sale, può essere ottenuto mediante un procedimento comprendente l’alchilazione di un composto di formula (VIII), o un suo sale In particular, a compound of formula (I), or a salt thereof, can be obtained by a process comprising the alkylation of a compound of formula (VIII), or a salt thereof
O OR
C OW C OW
N H N N H N
(VIII) (VIII)
dove W à ̈ un gruppo -OH oppure un gruppo -OR1, dove R1à ̈ un gruppo C1-C6alchile lineare oppure ramificato, oppure -NH2, con un composto di formula (II) così ottenuto, dove X à ̈ un gruppo uscente come sopra definito e P à ̈ H oppure un gruppo protettivo dell’azoto indolico come sopra definito, ad ottenere un composto di formula (IX) o un suo sale where W is a -OH group or an -OR1 group, where R1 is a linear or branched C1-C6alkyl group, or -NH2, with a compound of formula (II) thus obtained, where X is a leaving group such as defined above and P à ̈ H or a protective group of indole nitrogen as defined above, to obtain a compound of formula (IX) or one of its salt
NOCOW NOCOW
N No.
N No.
N No.
P (IX) P (IX)
dove W e P sono come sopra definiti, e, se il caso, la conversione di un composto di formula (IX) in un altro composto di formula (IX), e/o la rimozione del gruppo protettivo ad ottenere un composto di formula (I) o un suo sale. where W and P are as defined above, and, if the case, the conversion of a compound of formula (IX) into another compound of formula (IX), and / or the removal of the protective group to obtain a compound of formula ( I) or one of its salt.
La reazione di alchilazione tra un composto di formula (II) e un composto di formula (VIII) ad ottenere un composto di formula (IX) e la successiva reazione di conversione a Vilazodone di formula (I) à ̈ ad esempio descritta in US 5,532,241 o in Org. Process Res. Dev. 2012, 16, 1552−1557 o in J. Med. Chem. 2004, 47, 4684-4692. The alkylation reaction between a compound of formula (II) and a compound of formula (VIII) to obtain a compound of formula (IX) and the subsequent conversion reaction to Vilazodone of formula (I) is described for example in US 5,532,241 or in Org. Process Res. Dev. 2012, 16, 1552âˆ'1557 or in J. Med. Chem. 2004, 47, 4684-4692.
La conversione di un composto di formula (IX) in un altro composto di formula (IX) può essere effettuata mediante le metodiche note nell’arte, ad esempio come descritto in US 5,532,241 o in Org. Process Res. Dev. 2012, 16, 1552−1557 o in J. Med. Chem. 2004, 47, 4684-4692. The conversion of a compound of formula (IX) into another compound of formula (IX) can be carried out by means of the methods known in the art, for example as described in US 5,532,241 or in Org. Process Res. Dev. 2012, 16, 1552âˆ'1557 or in J. Med. Chem. 2004, 47, 4684-4692.
Un sale di un composto di formula (VIII) o (IX) o (I) in accordo alla presente invenzione à ̈ preferibilmente un loro sale farmaceuticamente accettabile noto. A salt of a compound of formula (VIII) or (IX) or (I) according to the present invention is preferably a known pharmaceutically acceptable salt thereof.
Un composto di formula (III) può essere preparato per reazione tra un composto di formula (V) A compound of formula (III) can be prepared by reaction between a compound of formula (V)
N No.
Y Y
N No.
P (V) P (V)
dove Y Ã ̈ un alogeno, preferibilmente bromo o iodio, oppure un gruppo OSO2R, dove R Ã ̈ ad esempio, metile, etile, fenile, benzile, p-tolile, pbromobenzile, p-nitrobenzile, trifluorometile, nonafluorobutile, N-imidazolo, preferibilmente metile; e P Ã ̈ come sopra definito, con un composto di formula (VI) where Y is a halogen, preferably bromine or iodine, or an OSO2R group, where R is for example, methyl, ethyl, phenyl, benzyl, p-tolyl, pbromobenzyl, p-nitrobenzyl, trifluoromethyl, nonafluorobutyl, N-imidazole, preferably methyl; and P is as defined above, with a compound of formula (VI)
X X
(VI) (YOU)
dove X Ã ̈ come sopra definito, nelle condizioni della reazione di Heck, ben nota alla persona esperta del ramo. where X is as defined above, under the conditions of the Heck reaction, well known to the person skilled in the art.
Ad esempio la reazione di Heck tra un composto di formula (V) ed un composto di formula (VI) può essere effettuata in presenza di un catalizzatore a base di Pd(0), preformato o generato in situ a partire da un sale di Pd(II), in particolare PdCl2o Pd(OAc)2, se desiderato in presenza di un legante quale, ad esempio, la trifenilfosfina, e di una base organica o inorganica, in particolare un’ammina secondaria o terziaria, opzionalmente in presenza di un solvente quale, ad esempio, un solvente dipolare aprotico, tipicamente dimetilformammide, dimetilacetammide, acetonitrile, dimetilsolfossido. For example, the Heck reaction between a compound of formula (V) and a compound of formula (VI) can be carried out in the presence of a catalyst based on Pd (0), preformed or generated in situ starting from a salt of Pd (II), in particular PdCl2 or Pd (OAc) 2, if desired in the presence of a binder such as, for example, triphenylphosphine, and of an organic or inorganic base, in particular a secondary or tertiary amine, optionally in the presence of a solvent such as, for example, an aprotic dipolar solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide.
Un composto di formula (IV) può essere preparato per reazione tra un composto di formula (V), come sopra definito, con un composto di formula (VII), A compound of formula (IV) can be prepared by reaction between a compound of formula (V), as defined above, with a compound of formula (VII),
X X
(VII) (VII)
dove X Ã ̈ come sopra definito, nelle condizioni della reazione di Sonogashira, ben nota alla persona esperta del ramo. where X is as defined above, under the conditions of the Sonogashira reaction, well known to the person skilled in the art.
Ad esempio, la reazione di Sonogashira tra un composto di formula (V) ed un composto di formula (VII) può essere effettuata in presenza di un catalizzatore a base di Pd(0), preformato o generato in situ a partire da un sale di Pd(II), in particolare PdCl2o Pd(OAc)2, se desiderato in presenza di un legante quale, ad esempio, la trifenilfosfina, se desiderato di un cocatalizzatore a base di Cu(I), ad esempio CuI e di una base organica o inorganica, in particolare un’ammina secondaria o terziaria, opzionalmente in presenza di un solvente quale, ad esempio, un solvente dipolare aprotico, tipicamente dimetilformammide (DMF), dimetilacetammide, acetonitrile, dimetilsolfossido. For example, the Sonogashira reaction between a compound of formula (V) and a compound of formula (VII) can be carried out in the presence of a catalyst based on Pd (0), preformed or generated in situ starting from a salt of Pd (II), in particular PdCl2 or Pd (OAc) 2, if desired in the presence of a binder such as, for example, triphenylphosphine, if desired, a Cu (I) -based cocatalyst, for example CuI and an organic base or inorganic, in particular a secondary or tertiary amine, optionally in the presence of a solvent such as, for example, an aprotic dipolar solvent, typically dimethylformamide (DMF), dimethylacetamide, acetonitrile, dimethylsulfoxide.
I composti di formula (III) e di formula (IV) sono nuovi e costituiscono un ulteriore oggetto della presente invenzione e sono utili nella preparazione di un composto di formula (IX) o (I) o un loro sale come sopra definiti. The compounds of formula (III) and of formula (IV) are new and constitute a further object of the present invention and are useful in the preparation of a compound of formula (IX) or (I) or a salt thereof as defined above.
I composti di formula (VI) e di formula (VII) sono disponibili commercialmente. The compounds of formula (VI) and formula (VII) are commercially available.
Il composto di formula (V) può essere preparato secondo metodiche riportate in letteratura e ben note alla persona esperta del ramo, ad esempio come riportato in US 7,105,516. The compound of formula (V) can be prepared according to methods reported in the literature and well known to the person skilled in the art, for example as reported in US 7,105,516.
Il seguenti esempi illustrano ulteriormente l’invenzione. The following examples further illustrate the invention.
Esempio 1: Sintesi di 3-iodo-1H-indolo-5-carbonitrile (V) Example 1: Synthesis of 3-iodo-1H-indole-5-carbonitrile (V)
1H-indolo-5-carbonitrile (5 g, 35.2 mmol), KOH (7.90 g, 141 mmol) and I2(8.90 g, 35.2 mmol) sono sospesi in 25 mL di DMF sotto atmosfera inerte. La reazione à ̈ mantenuta in agitazione al buio per 30 min. a 10°C, quindi trattata con una soluzione di Na2S2O30,1M (150 mL). La sospensione così ottenuta à ̈ mantenuta in agitazione per 30 min, quindi filtrata ed il solido ottenuto lavato con acqua e seccato a 50°C sotto vuoto fino a peso costante. Si ottiene il prodotto (V) (9.0 g) come solido bianco con una resa del 95%. 1H-indole-5-carbonitrile (5 g, 35.2 mmol), KOH (7.90 g, 141 mmol) and I2 (8.90 g, 35.2 mmol) are suspended in 25 mL of DMF under an inert atmosphere. The reaction is kept stirred in the dark for 30 min. at 10 ° C, then treated with a Na2S2O30,1M solution (150 mL). The suspension thus obtained is kept under stirring for 30 min, then filtered and the solid obtained washed with water and dried at 50 ° C under vacuum to constant weight. The product (V) (9.0 g) is obtained as a white solid with a yield of 95%.
<1>H-NMR (400 MHz, CDCl3), Î ́: 8.78 (1H, bs); 7.80 (1H, s); 7.46-7.40 (3H, m). <1> H-NMR (400 MHz, CDCl3), Î ́: 8.78 (1H, bs); 7.80 (1H, s); 7.46-7.40 (3H, m).
Esempio 2: Sintesi di 3-iodo-1-tosil-1H-indolo-5-carbonitrile (V) Il 3-iodo-1H-indolo-5-carbonitrile (V) ottenuto come in Esempio 1 (8.7 g, 32.5 mmol), NaOH (2.1 g, 52.5 mmol), trietilbenzilammonio cloruro (0.7 g, 3.1 mmol) e cloruro di tosile (6.7g, 35.1 mmol) sono sospesi in CH2Cl2(260 mL) sotto atmosfera inerte e la miscela di reazione à ̈ mantenuta in agitazione a temperatura ambiente per una notte. La miscela à ̈ trattata con acqua e le fasi separate. La fase organica à ̈ ulteriormente lavata con acqua ed una soluzione di NaCl saturo quindi anidrificata su Na2SO4, filtrata e concentrata a pressione ridotta. Si ottiene così il prodotto (V) come solido (12.5 g) con una resa del 91%. Example 2: Synthesis of 3-iodo-1-tosyl-1H-indole-5-carbonitrile (V) The 3-iodo-1H-indole-5-carbonitrile (V) obtained as in Example 1 (8.7 g, 32.5 mmol) , NaOH (2.1 g, 52.5 mmol), triethylbenzylammonium chloride (0.7 g, 3.1 mmol) and tosyl chloride (6.7g, 35.1 mmol) are suspended in CH2Cl2 (260 mL) under an inert atmosphere and the reaction mixture is kept in stirring at room temperature overnight. The mixture is treated with water and the phases separated. The organic phase is further washed with water and a saturated NaCl solution then dried over Na2SO4, filtered and concentrated at reduced pressure. The product (V) is thus obtained as a solid (12.5 g) with a yield of 91%.
<1>H-NMR (400 MHz, CDCl3), Î ́: 8.02 (1H, d, J= 8.4 Hz); 7.78-7.54 (3H, m); 7.69 (1H, s); 7.58 (1H, d, J= 8.4 Hz); 7.26 (2H; d, J= 8.0 Hz); 2.34 (3H, s). <1> H-NMR (400 MHz, CDCl3), Î ́: 8.02 (1H, d, J = 8.4 Hz); 7.78-7.54 (3H, m); 7.69 (1H, s); 7.58 (1H, d, J = 8.4 Hz); 7.26 (2H; d, J = 8.0 Hz); 2.34 (3H, s).
Esempio 3: Sintesi di 3-(4-idrossibut-1-inil)-1-tosil-1H-indolo-5-carbonitrile (IV) Example 3: Synthesis of 3- (4-hydroxybut-1-yl) -1-tosyl-1H-indole-5-carbonitrile (IV)
Il 3-iodo-1-tosil-1H-indolo-5-carbonitrile (V) (12.5 g, 28.3 mmol), PdCl2(150 mg, 0,85 mmol), PPh3(668 mg, 2.55 mmol), CuI (162 mg, 0.85 mmol) sono sospesi in una miscela di trietilammina (65 mL) e DMF (60 mL) sotto atmosfera inerte. La miscela à ̈ stata portata alla temperatura di 30°C, quindi trattata con una soluzione (10 mL) ottenuta disciogliendo il 3-butin-1-ol (2.7 mL, 30.0 mmol) in DMF aggiunta per lento gocciolamento. A fine aggiunta la miscela di reazione à ̈ lasciata rinvenire a temperatura ambiente e mantenuta sotto agitazione per una notte. La miscela à ̈ stata quindi diluita con etile acetato (200 mL) e trattata con una soluzione di HCl 1M fino a netta acidità . Le fasi sono separate e quella organica à ̈ lavata nell’ordine con una soluzione di NaHCO3satura addizionata di una soluzione al 33% di NH4OH, una soluzione di Na2S2O30,1M e una soluzione satura di NaCl. La fase organica à ̈ seccata su Na2SO4, filtrata, concentrata a pressione ridotta. Si ottiene il prodotto (IV) grezzo come solido (11 g) che non viene purificato ma impiegato come tale nella reazione successiva. Una aliquota di prodotto grezzo à ̈ purificata mediante cromatografia flash (etere di petrolio/AcOEt 50/50) ottenendo il prodotto (IV) chimicamente puro come solido bianco. 3-iodo-1-tosyl-1H-indole-5-carbonitrile (V) (12.5 g, 28.3 mmol), PdCl2 (150 mg, 0.85 mmol), PPh3 (668 mg, 2.55 mmol), CuI (162 mg, 0.85 mmol) are suspended in a mixture of triethylamine (65 mL) and DMF (60 mL) under an inert atmosphere. The mixture was brought to a temperature of 30 ° C, then treated with a solution (10 mL) obtained by dissolving 3-butin-1-ol (2.7 mL, 30.0 mmol) in DMF added by slow dripping. At the end of the addition, the reaction mixture is left to reach room temperature and kept under stirring overnight. The mixture was then diluted with ethyl acetate (200 mL) and treated with a 1M HCl solution until clear acidity. The phases are separated and the organic one is washed in order with a solution of NaHCO3saturated with the addition of a 33% solution of NH4OH, a solution of Na2S2O30.1M and a saturated solution of NaCl. The organic phase is dried on Na2SO4, filtered, concentrated at reduced pressure. The crude product (IV) is obtained as a solid (11 g) which is not purified but used as such in the subsequent reaction. An aliquot of crude product is purified by flash chromatography (petroleum ether / AcOEt 50/50) obtaining the chemically pure product (IV) as a white solid.
<1>H-NMR (400 MHz, CDCl3), Î ́: 7.97 (1H, d, J= 8.4 Hz); 7.89 (1H, s); 7.71 - 7.68 (3H, m); 7.50 (1H, d, J= 8.8 Hz); 7.20 (1H, d, J= 8.4 Hz); 3.78 (2H, m); 3.65 (1H, bs); 2.67 (2H, t, J= 6.4 Hz); 2.29 (3H, s). <1> H-NMR (400 MHz, CDCl3), Î ́: 7.97 (1H, d, J = 8.4 Hz); 7.89 (1H, s); 7.71 - 7.68 (3H, m); 7.50 (1H, d, J = 8.8 Hz); 7.20 (1H, d, J = 8.4 Hz); 3.78 (2H, m); 3.65 (1H, bs); 2.67 (2H, t, J = 6.4 Hz); 2.29 (3H, s).
Esempio 4: 3-(4-Idrossibutil)-1-tosil-1H-indolo-5-carbonitrile (II) Il 3-(4-idrossibutin-1-il)-1-tosil-1H-indolo-5-carbonitrile (IV) grezzo, preparato come in Esempio 3, (1.42 g, 3.90 mmol) disciolto in MeOH (30 mL) à ̈ trattato con Pd(OH)2/C 20% w/w (281 mg). Il sistema à ̈ inertizzato e lasciato ad agitare per una notte sotto atmosfera di H2a pressione ambiente. La miscela di fine reazione à ̈ quindi filtrata su Celite<®>e la soluzione concentrata a pressione ridotta. Il prodotto grezzo à ̈ purificato mediante cromatografia flash (etere di petrolio/AcOEt: 50/50) ottenendo il composto di formula (II) come solido (1.48 g) chimicamente puro con una resa del 96%. Example 4: 3- (4-Hydroxybutyl) -1-tosyl-1H-indole-5-carbonitrile (II) The 3- (4-hydroxybutin-1-yl) -1-tosyl-1H-indole-5-carbonitrile ( IV) crude, prepared as in Example 3, (1.42 g, 3.90 mmol) dissolved in MeOH (30 mL) is treated with Pd (OH) 2 / C 20% w / w (281 mg). The system is inerted and left to stir overnight under H2a ambient pressure. The end-of-reaction mixture is then filtered on Celite <®> and the concentrated solution under reduced pressure. The crude product is purified by flash chromatography (petroleum ether / AcOEt: 50/50) obtaining the compound of formula (II) as a chemically pure solid (1.48 g) with a yield of 96%.
<1>H-NMR (400 MHz, CDCl3), Î ́: 7.99 (1H, d, J= 8.4 Hz); 7.76 (1H, s); 7,78 (2H, d, J= 8.8 Hz); 7.47 (2H, d, J= 8.4 Hz); 7.40 (1H, s); 7.19 (2H, d, J= 8.4 Hz); 3.50 (2H, m), 2.63 (2H, t, J= 7 Hz); 1.73 – 1.68 (2H, m); 1.61 – 1.56 (2H, m). <1> H-NMR (400 MHz, CDCl3), Î ́: 7.99 (1H, d, J = 8.4 Hz); 7.76 (1H, s); 7.78 (2H, d, J = 8.8 Hz); 7.47 (2H, d, J = 8.4 Hz); 7.40 (1H, s); 7.19 (2H, d, J = 8.4 Hz); 3.50 (2H, m), 2.63 (2H, t, J = 7 Hz); 1.73 â € “1.68 (2H, m); 1.61 â € “1.56 (2H, m).
Esempio 5: Sintesi di 4-(5-ciano-1-tosil-1H-indol-3-il)butil metansolfonato (II) Example 5: Synthesis of 4- (5-cyano-1-tosyl-1H-indole-3-yl) butyl methanesulfonate (II)
Il 3-(4-idrossibutil)-1-tosil-1H-indolo-5-carbonitrile (II) (486 mg, 1.32 mmol) preparato come in Esempio 4 à ̈ disciolto in CH2Cl2(15 mL) in presenza di Et3N (277 µL, 1.98 mmol) sotto atmosfera inerte. La soluzione à ̈ portata a 0°C e trattata con cloruro di mesile (156 µL, 1.58 mmol). La miscela di reazione à ̈ mantenuta in agitazione per 1h a temperatura ambiente quindi trattata nell’ordine con una soluzione di HCl 1M, NaHCO3saturo, ed infine con una soluzione satura di NaCl. La fase organica à ̈ anidrificata su Na2SO4, concentrata a pressione ridotta ed il residuo purificato mediante cromatografia flash (etere di petrolio/AcOEt 50/50). Si ottiene il prodotto (II) (519 mg, 1.16 mmol) come solido con una resa dell’88%. The 3- (4-hydroxybutyl) -1-tosyl-1H-indole-5-carbonitrile (II) (486 mg, 1.32 mmol) prepared as in Example 4 is dissolved in CH2Cl2 (15 mL) in the presence of Et3N (277 µL, 1.98 mmol) under an inert atmosphere. The solution is brought to 0 ° C and treated with mesyl chloride (156 µL, 1.58 mmol). The reaction mixture is kept under stirring for 1 hour at room temperature and then treated in the order with a solution of 1M HCl, NaHCO3saturated, and finally with a saturated solution of NaCl. The organic phase is anhydrified on Na2SO4, concentrated at reduced pressure and the residue purified by flash chromatography (petroleum ether / AcOEt 50/50). The product (II) (519 mg, 1.16 mmol) is obtained as a solid with a yield of 88%.
<1>H-NMR (400 MHz, CDCl3), Î ́: 8.01 (1H, d, J= 8.6); 7.77 (1H, s); 7.71 (2H, d, J= 8.2 Hz); 7.51 (1H, d, J= 8.6 Hz); 7.42 (1H, s); 7.21 (2H, d, J= 8.2 Hz); 4.23 (2H, t, J= 5.2 Hz); 2.98 (3H, s); 2.67 (2H, m); 2.31 (3H, s); 1.78 1.77 (2H, m). <1> H-NMR (400 MHz, CDCl3), Î ́: 8.01 (1H, d, J = 8.6); 7.77 (1H, s); 7.71 (2H, d, J = 8.2 Hz); 7.51 (1H, d, J = 8.6 Hz); 7.42 (1H, s); 7.21 (2H, d, J = 8.2 Hz); 4.23 (2H, t, J = 5.2 Hz); 2.98 (3H, s); 2.67 (2H, m); 2.31 (3H, s); 1.78 1.77 (2H, m).
Esempio 6: Sintesi di Etil 5-(4-(4-(5-ciano-1-tosil-1H-indol-3-il)butil)piperazin-1-il)benzofuran-2-carbossilato (IX), con P= tosile e W= -OEt Example 6: Synthesis of Ethyl 5- (4- (4- (5-cyano-1-tosyl-1H-indol-3-yl) butyl) piperazin-1-yl) benzofuran-2-carboxylate (IX), with P = tosyl and W = -OEt
Il 4-(5-ciano-1-tosil-1H-indol-3-il)butil metansolfonato (II) (100 mg, 0.22 mmol), preparato come descritto in Esempio 5 e l’etil 5-(piperazin-1-il)benzofuran-2-carbossilato di formula (VIII) (62 mg, 0.22 mmol) sono disciolti in CH3CN (4 mL) e trattati con K2CO3(91 mg, 0.66 mmol) sotto atmosfera inerte. La miscela di reazione à ̈ mantenuta in agitazione alla temperature di riflusso per una notte quindi diluita con AcOEt e H2O. Le fasi sono separate e quella organica à ̈ anidrificata su Na2SO4, concentrata a pressione ridotta ed il residuo purificato mediante cromatografia flash (etere di petrolio/AcOEt 50/50). Si ottiene l’etil 5-(4-(4-(5-ciano-1-tosil-1H-indol-3-il)butil)piperazin-1-il)benzo furan-2-carbossilato (97 mg, 0.16 mmol) di formula (IX) chimicamente puro con una resa del 72%. 4- (5-cyano-1-tosyl-1H-indol-3-yl) butyl methanesulfonate (II) (100 mg, 0.22 mmol), prepared as described in Example 5, and ethyl 5- (piperazin-1 -yl) benzofuran-2-carboxylate of formula (VIII) (62 mg, 0.22 mmol) are dissolved in CH3CN (4 mL) and treated with K2CO3 (91 mg, 0.66 mmol) under an inert atmosphere. The reaction mixture is kept under stirring at the reflux temperature for one night and then diluted with AcOEt and H2O. The phases are separated and the organic one is dried over Na2SO4, concentrated at reduced pressure and the residue purified by flash chromatography (petroleum ether / AcOEt 50/50). Ethyl 5- (4- (4- (5-cyano-1-tosyl-1H-indol-3-yl) butyl) piperazin-1-yl) benzo furan-2-carboxylate (97 mg, 0.16 mmol) of chemically pure formula (IX) with a yield of 72%.
<1>H-NMR (400 MHz, CDCl3), Î ́: 8.01 (1H, d, J= 8.4 Hz); 7.78 (1H, s); 7.71 (2H, d, J= 8.4 Hz); 7.51 (1H, d, J= 8.2 Hz); 7,44-7.40 (3H, m); 7.21 (2H, d, J= 8.4 Hz); 7.13 (1H, dd, J=9.2, 2.4 Hz); 7.07 (1H, s); 4.39 (2H, q, J= 7.2 Hz); 3.15 (4H, t, J= 4.8 Hz); 2.66 (2H, t, J= 7.4 Hz); 2.59 (4H, t, J= 4.8 Hz); 2.41 (2H, t, J= 7.4 Hz); 2.31 (3H, s); 1.74-1.66 (1H, m); 1.61-1.56 (1H, m); 1.38 (3H, t, J= 7.2 Hz). <1> H-NMR (400 MHz, CDCl3), Î ́: 8.01 (1H, d, J = 8.4 Hz); 7.78 (1H, s); 7.71 (2H, d, J = 8.4 Hz); 7.51 (1H, d, J = 8.2 Hz); 7.44-7.40 (3H, m); 7.21 (2H, d, J = 8.4 Hz); 7.13 (1H, dd, J = 9.2, 2.4 Hz); 7.07 (1H, s); 4.39 (2H, q, J = 7.2 Hz); 3.15 (4H, t, J = 4.8 Hz); 2.66 (2H, t, J = 7.4 Hz); 2.59 (4H, t, J = 4.8 Hz); 2.41 (2H, t, J = 7.4 Hz); 2.31 (3H, s); 1.74-1.66 (1H, m); 1.61-1.56 (1H, m); 1.38 (3H, t, J = 7.2 Hz).
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WO2006061379A1 (en) * | 2004-12-08 | 2006-06-15 | Solvay Pharmaceuticals B.V. | Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition |
Family Cites Families (3)
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DE4333254A1 (en) | 1993-09-30 | 1995-04-06 | Merck Patent Gmbh | Piperidines and piperazines |
TW200418838A (en) | 2002-09-18 | 2004-10-01 | Bristol Myers Squibb Co | Compounds for the treatment of premature ejaculation |
US20140350255A1 (en) * | 2012-02-01 | 2014-11-27 | Ranbaxy Laboratories Limited | Process for the preparation of vilazodone or its pharmaceutically acceptable salts |
-
2013
- 2013-03-15 IT IT000392A patent/ITMI20130392A1/en unknown
-
2014
- 2014-03-12 US US14/205,684 patent/US20140275542A1/en not_active Abandoned
- 2014-03-13 EP EP14159607.2A patent/EP2778165A1/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006061379A1 (en) * | 2004-12-08 | 2006-06-15 | Solvay Pharmaceuticals B.V. | Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition |
Non-Patent Citations (1)
Title |
---|
BIN HU ET AL: "Scale-Up Synthesis of Antidepressant Drug Vilazodone", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 16, no. 9, 21 September 2012 (2012-09-21), pages 1552 - 1557, XP055061951, ISSN: 1083-6160, DOI: 10.1021/op300171m * |
Also Published As
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EP2778165A1 (en) | 2014-09-17 |
US20140275542A1 (en) | 2014-09-18 |
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